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The present invention provides compounds of Formula (I): (Formula (I), or
a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein
all of the variables are as defined herein. These compounds are GPR40 G
protein-coupled receptor modulators which may be used as medicaments.
##STR00001##

The present application is a 371 of International Application No.
PCT/US2013/070216 filed on Nov. 15, 2013, which claims priority benefit
of U.S. provisional application Ser. No. 61/727,262, filed Nov. 16, 2012;
each of which is fully incorporated by reference herein.

The present invention provides novel carboxylic acid substituted dihydropyrazole compounds, and their analogues thereof, which are GPR40 G protein-coupled receptor modulators, compositions containing them, and methods of using them, for example,
for the treatment or prophylaxis of diabetes and related conditions.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a progressively debilitating disorder of epidemic proportions leading to various micro- and macrovascular complications and morbidity. The most common type of diabetes, type 2 diabetes, is characterized by increasing
insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. Free fatty acids (FFAs) are evidenced to influence insulin secretion from .beta. cells primarily by enhancing glucose-stimulated insulin
secretion (GSIS). G-protein coupled receptors (GPCRs) expressed in .beta. cells are known to modulate the release of insulin in response to changes in plasma glucose levels. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane-bound FFA
receptor which is preferentially expressed in the pancreatic islets and specifically in .beta. cells and mediates medium to long chain fatty acid induced insulin secretion. GPR40 is also expressed in enteroendocrine cells wherein activation promotes
the secretion of gut incretin hormones, such as GLP-1, GIP, CCK and PYY. To decrease medical burden of type 2 diabetes through enhanced glycemic control, GPR40 modulator compounds hold the promise of exerting an incretin effect to promote GSIS as well
as potential combination with a broad range of antidiabetic drugs.

The present invention relates to novel substituted dihydropyrazole compounds which have the ability to modulate GPR40. Such compounds are therefore potentially useful for the treatment or prophylaxis of diabetes and related conditions.

SUMMARY OF THE INVENTION

The present invention provides substituted dihydropyrazole compounds, and their analogues thereof, which are useful as GPR40 modulators, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or
solvates thereof.

The compounds of the invention may be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40, such as diabetes and related conditions, microvascular complications associated with diabetes, the
macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, disorders of glucose metabolism, obesity and other maladies.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40.

The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

Other features and advantages of the invention will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by reference to the accompanying drawings described below.

R.sup.11, at each occurrence, is independently selected from: H, C.sub.1-4 alkyl and benzyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

In a fifth aspect, the present disclosure provides the compound of the fourth aspect wherein the compound of the second aspect is excluded.

In a sixth aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, third, fourth and fifth aspects,
wherein:

In an eighth aspect, the present disclosure provides the compound of the first aspect wherein the compound of the seventh aspect is excluded.

In a ninth aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, third, fourth, fifth, sixth and
eighth aspects, wherein:

In an eleventh aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, within the scope of any of the first, third, fourth, fifth, sixth,
eighth, ninth and tenth aspects, wherein:

In another embodiment, R.sup.6, at each occurrence, is independently selected from: halogen, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy.

In another embodiment, R.sup.6, at each occurrence, is independently selected from: halogen and C.sub.1-4 alkyl.

In another embodiment, R.sup.6, at each occurrence, is independently selected from: halogen and C.sub.1-4 alkoxy.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values .ltoreq.10 .mu.M.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values .ltoreq.5 .mu.M.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values .ltoreq.1 .mu.M.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values .ltoreq.0.5 .mu.M.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values .ltoreq.0.2 .mu.M.

In another embodiment, the compounds of the present invention have hGPR40 EC.sub.50 values 0.1 .mu.M.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process for making a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediate for making a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agents are, for example, an SGLT2 inhibitor (for example a member selected from dapagliflozin, canagliflozin, empagliflozin
and remagliflozin).

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40, comprising administering to a patient in need of such treatment and/or prophylaxis a
therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diabetes, hyperglycemia, gestational diabetes, obesity, dyslipidemia, hypertension and cognitive impairment, comprising administering to a
patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one
other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diabetes, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least
one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of hyperglycemia, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at
least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of obesity, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one
of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of dyslipidemia, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at
least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of hypertension, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at
least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of cognitive impairment, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of
at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides a compound of the present invention for use in therapy for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40.

In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40.

In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40, comprising: administering to a patient in need thereof a therapeutically effective
amount of a first and second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention. Preferably, the second therapeutic agent, for example, a DPP4 inhibitor (for example a member selected from saxagliptin,
sitagliptin, vildagliptin, linagliptin and alogliptin).

In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple
diseases or disorders associated with GPR40.

Where desired, the compound of the present invention may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in
a separate oral dosage form or by injection. The other type of antidiabetic agent that may be optionally employed in combination with the GPR40 receptor modulator of the present invention may be one, two, three or more antidiabetic agents or
antihyperglycemic agents which may be administered orally in the same dosage form, in a separate oral dosage form, or by injection to produce an additional pharmacological benefit.

The GPR40 receptor modulator of the present invention may also be optionally employed in combination with agents for treating complication of diabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of the present invention may also be optionally employed in combination with one or more hypophagic and/or weight-loss agents such as diethylpropion, phendimetrazine, phentermine, orlistat, sibutramine, lorcaserin,
pramlintide, topiramate, MCHR1 receptor antagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat, 5HT2c receptor modulators, and the like. The GPR40 receptor
modulator of the present invention may also be employed in combination with an agonist of the glucagon-like peptide-1 receptor (GLP-1 R), such as exenatide, liraglutide, GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37), which may be administered via
injection, intranasal, or by transdermal or buccal devices.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood
that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent
embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C.dbd.C double bonds, C.dbd.N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated
in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in
optically active or racemic forms. Optically active forms may be prepared by resolution of stereoisomeric forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates
made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the
process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be
converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently
rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C.sub.1 to C.sub.6 alkyl" or "C.sub.1-6
alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl
(e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C.sub.0 alkyl" or "C.sub.0 alkylene" is used, it is intended to denote a direct bond.

Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any
stable point along the chain. For example, "C.sub.2 to C.sub.6 alkenyl" or "C.sub.2-6 alkenyl" (or alkenylene), is intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkenyl groups. Examples of alkenyl include, but are not limited to,
ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

The term "alkoxy" or "alkyloxy" refers to an --O-alkyl group. For example, "C.sub.1 to C.sub.6 alkoxy" or "C.sub.1-6 alkoxy" (or alkyloxy), is intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkoxy groups. Example
alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached
through a sulphur bridge; for example methyl-S-- and ethyl-S--.

"Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more
halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.

"Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C.sub.1-6 haloalkoxy", is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as
defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S--, and pentafluoroethyl-S--.

The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. For example, "C.sub.3 to C.sub.6 cycloalkyl" or "C.sub.3-6 cycloalkyl" is intended to include C.sub.3, C.sub.4, C.sub.5, and C.sub.6
cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition
of "cycloalkyl". The term "cycloalkenyl" refers to cyclized alkenyl groups. C.sub.4-6 cycloalkenyl is intended to include C.sub.4, C.sub.5, and C.sub.6 cycloalkenyl groups. Example cycloalkenyl groups include, but are not limited to, cyclobutenyl,
cyclopentenyl, and cyclohexenyl.

As used herein, "carbocycle," "carbocyclyl," or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which
may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,
adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As
shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl.
When the term "carbocycle" is used, it is intended to include "aryl." A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a
bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring
is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results
in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl,
1,2,3,4-tetrahydronaphthyl, and indanyl.

The term "benzyl," as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group.

As used herein, the term "heterocycle," "heterocyclyl," or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that
is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N.fwdarw.O and S(O).sub.p, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H
or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen
atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It
is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.

As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second
ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second
ring is a carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if
the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the
heterocycle is not more than 1.

Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include,
but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents
recited for the ring may also be present on the bridge.

The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), calcium (Ca.sup.2+)ammonium
(R.sub.nNH.sub.m+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a
hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Wuts, P. G. M. and Greene, T. W. Protecting Groups in Organic Synthesis, 4th
Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the
following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and
9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and
adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and
benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds,
as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N, or N.dbd.N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this
invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N.fwdarw.O) derivative.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted
with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to
the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium
salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and
nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid
or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are
preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22.sup.nd Edition, Allen, L. V. Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of
prodrugs are well known in the art. For examples of such prodrug derivatives, see:

Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in
many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable
esters of compounds of formula I include C.sub.1-6alkyl, C.sub.1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C.sub.1-6 alkanoyloxy-C.sub.1-6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl),
C.sub.1-6alkoxycarbonyloxy-C.sub.1-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for
example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

The present invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as .sup.2H (also represented as `D` for deuterium) and .sup.3H, carbon such as .sup.11C, .sup.13C, and .sup.14C,
nitrogen, such as .sup.13N and .sup.15N, oxygen, such as .sup.15O, .sup.17O, and .sup.18O. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, .sup.3H, and carbon-14, .sup.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as
deuterium, .sup.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with
positron emitting isotopes, such as .sup.11C, .sup.15O, .sup.18F, and .sup.13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the invention can generally be
prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be
capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The
solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates,
and isopropanolates. Methods of solvation are generally known in the art.

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent
or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be
consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions,
including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and
procedures for these reactions appear hereinafter and in the working examples. Protection and de-protection in the processes below may be carried out by procedures generally known in the art (see, for example, Wuts, P. G. M. and Greene, T. W. Protecting
Groups in Organic Synthesis, 4th Edition, Wiley (2007)). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. and Fleming, I., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in
Modern Organic Chemistry, Pergamon Press, New York, N.Y. (1991); Smith, M. B. and March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley & Sons, New York, N.Y. (2007); Katritzky, A. R. and Taylor, R. J.
K., eds., Comprehensive Organic Functional Groups Transformations II, 2nd Edition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y. (1999), and references therein.

Compounds of Formula (I) can be prepared as shown in Scheme 1. Conversion of hydrazine A, which contains a LG such as .dbd.F, Cl, Br and the like, to hydrazide B with trifluoroacetic anhydride followed by treatment with a phenylsulfonyl
chloride forms hydrazonoyl chloride C. Hydrazonoyl chloride C can undergo a [3+2] cycloaddition with an .alpha.,.beta.-unsaturated carbonyl compound where Y is a chiral auxiliary, such as (4S)-phenyloxazolidinone and the like, or alkoxy group to give
dihydropyrazole D as depicted in Scheme 1. Reduction of the carbonyl group in D, via a reducing agent, e.g., NaBH.sub.4 or LiBH.sub.4, leads to hydroxyl E. Activation of the hydroxyl group of E, via methanesulfonyl chloride, for example, and
displacement with a cyanide reagent, e.g., sodium cyanide, potassium cyanide or trimethylsilylcyanide, leads to nitrile F. Nitrile F can be converted to methyl ester G by acidic methanolysis. Intermediate G can be converted to boronate H by metal
catalyzed borylation, e.g, catalyzed by Pd(dppf)Cl.sub.2. Cleavage of the boronate group in H, via oxidation with, for example, H.sub.2O.sub.2, leads to phenol M. Displacement of the hydroxyl group in L (synthesis shown vide infra) with phenol M, via
e.g. PBu.sub.3 and ADDP, or PPh.sub.3 and DEAD, or PPh.sub.3 and DBAD, generates intermediate N. Intermediate N can be converted to compounds of Formula (I) by hydrolysis, via a hydroxide reagent, e.g, LiOH or NaOH. Intermediate L can be synthesized
from amine J. Conversion of the amine J to intermediate K via metal catalyzed amination or SN.sub.Ar reaction, e.g. Pd (0), Cu(I) or heat with base. Activation of X group in K, via toluenesulfonyl chloride, for example, leads to intermediate L.

##STR00044## ##STR00045##

Alternatively, compounds of Formula (I) may be synthesized starting with amine O; treatment of O with MeI affords ammonium salt P. Conversion of P to Q with R.sup.1NH.sub.2 and base (as described, for example, in David R. Tortolani, Michael A.
Poss, Organic Letters, 1999, Vol. 1, No. 8, 1261-1263) followed by treatment with reductant, e.g. L-selectride, forms alcohol S as shown in Scheme 2. Transformation of the hydroxyl group in S to leaving group gives intermediate L, via methanesulfonyl
chloride, for example. Intermediate L could be converted to compounds of Formula (I) according to the synthetic steps described in Scheme 1.

##STR00046##

Alternatively, compounds of Formula (I) can be synthesized via coupling T and U to afford intermediate V via metal catalyzed amination or SN.sub.Ar reaction, e.g. Pd (0), Cu(I) or heat with base as depicted in Scheme 3. Acid mediated
deprotection of V followed by olefination, for example Wittig reaction, e.g. methyltriphenylphosphonium bromide and nBuLi, forms olefin W. Coupling W and F by treatment with Pd(dppf)Cl.sub.2 and 9-BBN generates Y. Nitrile Y can be converted to the methyl
ester N by acidic methanolysis. Intermediate N could be converted to compounds of Formula (I) by hydrolysis, via a hydroxide reagent, e.g, LiOH or NaOH.

##STR00047##

Alternatively, compounds of Formula (I) can be synthesized via reaction of intermediate C with a substituted acrylate AA in the presence of a Ag salt to provide dihydropyrazole AB as depicted in Scheme 4. The methyl ester AB can be hydrolyzed,
via LiOH, for example, to afford carboxylic acid AC. Carboxylic acid AC can be converted to ester AD, via Arndt-Eistert homologation. Intermediate AD could be converted to compounds of Formula (I) by according to the synthetic steps described in Scheme
1 or Scheme 3.

##STR00048##

The compound of the instant invention herein described may have asymmetric centers. For example, the chiral carbon atoms in Formula (I) or Formula (II), as indicated below, exist in either as S or R configuration.

##STR00049##

Thus, the stereoisomeric configurations of each compound of Formula (I) or Formula (II) are considered part of the invention. In structures where the stereochemistry of an intermediate or final compound is not indicated, it has not been
determined.

IV. Biology

Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. It is diagnosed as a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood glucose. Diabetes is a syndrome with
interrelated metabolic, vascular, and neuropathic components. The metabolic abnormality is generally characterized by hyperglycemia and alterations in carbohydrate, fat and protein metabolism caused by absent or reduced insulin secretion and/or
ineffective insulin secretion. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of diabetic
syndrome. Strikingly, diabetes is the fourth leading cause of global death by disease, the largest cause of kidney failure in developed countries, the leading cause of vision loss in industrialized countries and has the greatest prevalence increase in
developing countries.

Type 2 diabetes, which accounts for 90% of diabetes cases, is characterized by increasing insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. The reasons for .beta. cell secondary
failure are not completely understood. Acquired pancreatic islet damage or exhaustion and/or genetic factors causing susceptibility to islet secretory insufficiency have been hypothesized.

Free fatty acids (FFAs) are evidenced to influence insulin secretion from .beta. cells primarily by enhancing glucose-stimulated insulin secretion (GSIS). Although glucose is recognized as the major stimulator of insulin secretion from .beta.
cells, other stimuli, such as amino acids, hormones, and FFAs, also regulate insulin secretion. Thus, under normal settings, insulin secretion from .beta. cells in response to food intake is evoked by the collective stimuli of nutrients, such as
glucose, amino acids, and FFAs, and hormones like the incretin glucagon-like peptide 1 (GLP-1). Fatty acids are also known to stimulate the secretion of several gut satiety hormones, including cholocystokinine (CCK), GLP-1, and peptide YY (PYY).

G-protein coupled receptors (GPCRs) expressed in .beta. cells are known to modulate the release of insulin in response to changes in plasma glucose levels. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane-bound FFA receptor
which is preferentially expressed in the pancreatic islets and specifically in .beta. cells. GPR40 (e.g., human GPR40, RefSeq mRNA ID NM_005303; e.g., mouse GPR40 RefSeq mRNA ID NM_194057) is a GPCR located at chromosome 19q13.12. GPR40 is activated
by medium to long chain fatty acids and thereby triggering a signaling cascade that results in increased levels of [Ca.sup.2+].sub.i in .beta. cells and subsequent stimulation of insulin secretion (Itoh et al., Nature, 422:173-176 (2003)). Selective
small molecule agonists of GPR40 have been shown to promote GSIS and reduce blood glucose in mice (Tan et al., Diabetes, 57:2211-2219 (2008)). Briefly, when activators of GPR40 are administered to either normal mice or mice that are prone to diabetes
due to genetic mutation, prior to a glucose tolerance test, improvements in glucose tolerance are observed. A short-lived increase in plasma insulin levels are also observed in these treated mice. It has also been shown that GPR40 agonists restore GSIS
in pancreatic .beta.-cells from the neonatal STZ rats suggesting that GPR40 agonists will be efficacious in diabetics with compromised .beta.-cell function and mass. Fatty acids are known to stimulate the secretion of several gut satiety hormones,
including cholocystokinine (CCK), GLP-1, and peptide YY (PYY), and GPR40 has been shown to colocalize with cells that secrete such hormones (Edfalk et al., Diabetes, 57:2280-2287 (2008) Luo et al. PLOSone, 7:1-12 (2012)). Fatty acids are also known to
play a role in neuronal development and function, and GPR40 has been reported as a potential modulator of the fatty acid effects on neurons (Yamashima, T., Progress in Neurobiology, 84:105-115 (2008)).

Given the increase in the worldwide patient population afflicted by type 2 diabetes, there is a need for novel therapies which are effective with minimal adverse events. To decrease medical burden of type 2 diabetes through enhanced glycemic
control, GPR40 modulator compounds of the present invention are being investigated here for their incretin effect to promote GSIS as well as the potential combination with a broad range of anti-diabetic drugs.

The term "modulator" refers to a chemical compound with capacity to either enhance (e.g., "agonist" activity) or partially enhance (e.g., "partial agonist" activity) or inhibit (e.g., "antagonist" activity or "inverse agonist" activity) a
functional property of biological activity or process (e.g., enzyme activity or receptor binding); such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, receptor
internalization, and/or may be manifest only in particular cell types.

It is also desirable and preferable to find compounds with advantageous and improved characteristics compared with known anti-diabetic agents, in one or more of the following categories that are given as examples, and are not intended to be
limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that decrease blood drug concentration peak-to-trough characteristics; (e) factors
that increase the concentration of active drug at the receptor; (f) factors that decrease the liability for clinical drug-drug interactions; (g) factors that decrease the potential for adverse side-effects, including selectivity versus other biological
targets; and (h) improved therapeutic index with less propensity for hypoglycemia.

As used herein, the term "patient" encompasses all mammalian species.

As used herein, the term "subject" refers to any human or non-human organism that could potentially benefit from treatment with a GPR40 modulator. Exemplary subjects include human beings of any age with risk factors for metabolic disease.
Common risk factors include, but are not limited to, age, sex, weight, family history, or signs of insulin resistance such as acanthosis nigricans, hypertension, dislipidemia, or polycystic ovary syndrome (PCOS).

As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; and/or (b) relieving the disease-state, i.e.,
causing regression of the disease state.

As used herein, "prophylaxis" or "prevention" cover the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are
selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

As used herein, "risk reduction" covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

"Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to modulate GPR40 and/or to prevent or treat the disorders listed herein.
When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

In Vitro GPR40 Assays

FDSS-based Intracellular Calcium Assay

Cell lines expressing GPR40 are generated using the pDEST 3.times.flag gene expression system and are cultured in culture medium comprising the following components: F12 (Gibco #11765), 10% lipid deprived fetal bovine serum, 250 .mu.g/ml zeocin
and 500 .mu.g/ml G418. To conduct the fluorescent imaging plate reader (FLIPR)-based calcium flux assay to measure intracellular Ca.sup.2+ response, cells expressing GPR40 are plated on 384 well plates (BD Biocoat #356697) at a density of 20,000
cells/20 .mu.L medium per well in phenol red and serum-free DMEM (Gibco #21063-029) and incubated overnight. Using BD kit #s 80500-310 or -301, the cells are incubated with 20 .mu.L per well of Hank's buffered salt solution with 1.7 mM probenecid and
Fluo-3 at 37.degree. C. for 30 min. Compounds are dissolved in DMSO and diluted to desired concentrations with assay buffer and added to the cells as 3.times. solution (20 .mu.L per well). Run fluorescence/luminescence reader FDSS (Hamamatsu) to read
intracellular Ca.sup.2+ response.

The exemplified Examples disclosed below were tested in the Human GRP40 In Vitro assay described above and found having hGRP40 modulating activity.

Test compounds were 3-fold, 11-point serially diluted in DMSO in a REMP assay plate (Matrix Cat. #: 4307) by BioCel (Agilent). The compounds were transferred into an Echo plate (LABCYTE, Cat. #: LP-0200) and 20 nL of diluted compounds were
transferred to an assay plate (proxi-plate from Perkin Elmer, Cat. #6008289) by Echo acoustic nano dispenser (LABCYTE, model ECHO550). 14 .mu.L of the diluted cells were then added to the assay plate by Thermo (SN 836 330) Combi Drop and incubated at
room temperature for 45 minutes. Then 3 .mu.L of IP1 coupled to dye D2 from the Cisbio IP-One kit were added to the assay plate followed by 3 .mu.L of Lumi4TM-Tb cryptate K from the kit. The plate was further incubated at room for 1 hour before reading
on the Envision (Perkin Elmer Model2101) with an HTRF protocol. Activation data for the test compound over a range of concentrations was plotted as percentage activation of the test compound (100%=maximum response). After correcting for background
[(sample read-mean of low control)/(mean of high control-mean of low control)] (low control is DMSO without any compound), EC50 values were determined. The EC50 is defined as the concentration of test compound which produces 50% of the maximal response
and was quantified using the 4 parameter logistic equation to fit the data. The maximal Y value observed (% Ymax) was calculated relative to a BMS standard reference compound at a final concentration of 0.625 .mu.M.

Some of the exemplified Examples disclosed below were tested in the Human GRP40 In Vitro assay described above and found having hGRP40 modulating activity reported as hGPR40 IP1 EC.sub.50.

In Vivo GPR40 Assays

Acute Oral Glucose Tolerance Test

Ten week old C57BL6 mice were housed individually and fasted for 5 hours on the day of study. Tail vein sampling was performed from nicked tails to obtain plasma samples. Baseline plasma samples were taken at t=0. Mice were orally treated
with vehicle or compounds co-administered with glucose (2 g/kg). Sampling thereafter from tails of treated mice at 20, 40, 60, 120 and 180 min provided data used for generating glucose excursion curves from which 0-180 min blood glucose excursion
profiles were generated. The area under the curve (AUC) allowed for assessment of glucose lowering by compound treatments. Blood samples were collected in EDTA-treated tubes (microvette CB300, Sarstedt, Numbrecht, Germany), stored on ice and spun @
6000 rpm for 10 minutes. Plasma glucose was analyzed on the same day using an AU680 Clinical Chemistry Analyzer (Beckman Coulter, Brea, Calif.). Statistical analysis is a one way ANOVA with Dunnett's post hoc test or two-way student's t test where
appropriate. P values less than 0.05 were considered statistically significant. Glucose reduction is reported as a % change in AUC (0-180 min) from the vehicle treatment group. For example, "Acute oral glucose tolerance: -50% @ 0.3 mg/kg" represents
the results of a study as described above, whereupon administration of 0.3 mg/kg of the specified example results in a 50% reduction in glucose AUC (0-180 min) relative to vehicle treated animals.

Acute Oral Glucose Tolerance Test in Rats

Male Sprague Dawley rats (CRL, Wilmington Mass.) were used. Rats were delivered to the vivarium and acclimated for 1 week. Rats were fasted from 5 PM on the night before study. Overnight fasted rats were 180-200 grams at time of study. Tail
vein sampling was performed to obtain baseline plasma samples. Rats were randomized to treatment groups based on fasting plasma glucose readings determined by Accu-Chek.RTM. glucometer (Roche, Indianapolis, Ind.). Rats were dosed at 4 mL/Kg body
weight with 40% PEG400 (Sigma, St. Louis, Mo.) 10% Cremophore (Sigma, St. Louis, Mo.) and 50% distilled water with or without compounds. For rats that received BMS DPP4i combined with GPR40 agonist, administration was performed by co-dosing compounds. Plasma samples were collected one hour after compound dosing to determine baseline changes in glucose and active GLP-1 levels in the presence and absence of BMS DPP4i. Sampling thereafter from tail veins provided time point data to calculate
AUC.sub.0-120' glucose as a marker of two hour glucose lowering efficacy. Blood samples were collected in EDTA-treated tubes (microvette CB300, Sarstedt, Numbrecht, Germany), stored on ice and spun @ 6000 rpm for 10 minutes. Plasma glucose was analyzed
on the same day using an AU680 Clinical Chemistry Analyzer (Beckman Coulter, Brea, Calif.). Statistical analysis is a one way ANOVA with Dunnett's post hoc test or two-way student's t test where appropriate. P values less than 0.05 were considered
statistically significant. Glucose reduction is reported as a % change in AUC (0-120 min) from the vehicle treatment group. Fasting hormone responses are the difference from basal levels 1 hour post dose. Active GLP-1 levels (GLP-1 (7-36) amide and
GLP-1 (7-37)) were measured by ELISA (Millipore, Billerica, Mass.).

BMS DPP4i was administered to rats alone, and in combination with Example 81, Isomer 2 of the present invention, at 10 mg/kg, as depicted in FIG. 1 and FIG. 2. As depicted in FIG. 1, the combination of BMS DPP4i with Example 81, Isomer 2
demonstrated greater reductions in plasma glucose during an oral glucose tolerance test than either Example 81, Isomer 2 or BMS DPP4i alone. As depicted in FIG. 2, the combination of BMS DPP4i with Example 81, Isomer 2 shows greater increases in active
GLP-1 during an oral glucose tolerance test than either Example 81, Isomer 2 or BMS DPP4i alone.

The compounds of the present invention possess activity as modulators of GPR40, and, therefore, may be used in the treatment of diseases associated with GPR40 activity. Via modulation of GPR40, the compounds of the present invention may
preferably be employed to modulate the production/secretion of insulin and/or gut hormones, such as GLP-1, GIP, PYY, CCK and amylin.

GPR40 is expressed in neuronal cells, and is associated with development and maintenance of neuronal health in brain, as described in Yamashima, T. Progress in Neurobiology 2008, 84, 105-115.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills,
powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal
injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment;
or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the
subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous
liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a
variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety
of readily available sources such as, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age,
sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect
desired.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most
preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose,
or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of
administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily
be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin
capsule.

A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of
physiological saline, to produce an injectable preparation.

The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a
pharmaceutical carrier. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other
pharmaceutically active material.

Where desired, the compound of the present invention may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in
a separate oral dosage form or by injection. The other type of antidiabetic agent that may be optionally employed in combination with the GPR40 receptor modulator of the present invention may be one, two, three or more antidiabetic agents or
antihyperglycemic agents which may be administered orally in the same dosage form, in a separate oral dosage form, or by injection to produce an additional pharmacological benefit.

The GPR40 receptor modulator of formula I may also be optionally employed in combination with agents for treating complication of diabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of formula I way also be optionally employed in combination with one or more hypophagic agents such as diethylpropion, phendimetrazine, phentermine, orlistat, sibutramine, lorcaserin, pramlintide, topiramate, MCHR1
receptor antagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat, 5HT2c receptor modulators, and the like. The compound of structure I may also be employed in
combination with an agonist of the glucagon-like peptide-1 receptor (GLP-1 R), such as exenatide, liraglutide, GPR-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is
incorporated herein by reference), which may be administered via injection, intranasal, or by transdermal or buccal devices. Reviews of current and emerging therapies for the treatment of obesity can be found in: Melnikova, I. et al., Nature Reviews
Drug Discovery, 5:369-370 (2006); Jones, D., Nature Reviews: Drug Discovery, 8:833-834 (2009); Obici, S., Endocrinology, 150(6):2512-2517 (2009); and Elangbam, C. S., Vet. Pathol., 46(1):10-24 (2009).

The above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents set out above, or as otherwise
determined by one of ordinary skill in the art.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined
in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be
enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal
tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and
also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another
approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl
methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner,
will be readily apparent to those skilled in the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" it is meant that the compound of the present invention
and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time.
Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the GPR40 receptor. Such compounds may be provided in a commercial kit, for
example, for use in pharmaceutical research involving GPR40 or anti-diabetic activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This
would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the
present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving GPR40.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a
first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
(c) a package insert stating that the pharmaceutical composition can be used for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40 (as defined previously). In another embodiment, the package insert states that the
pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment and/or prophylaxis of multiple diseases or disorders associated with GPR40. The article of manufacture can further comprise:
(d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container
holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask,
syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or
plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of
attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue,
staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the
area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package
insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the
desired information has been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary
meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may be prepared using the same.

Hplc/Ms and Preparatory/Analytical Hplc Methods Employed in Characterization or Purification of Examples

Preparatory HPLC (unless otherwise noted) was performed on a Shimadzu SCL-10A liquid chromatograph with a linear gradient of 20-100% Solvent B over 10 or 30 min, with either a 2 or 5 min (respectively) hold at 100% Solvent B;

UV visualization at 220 nm;

Column: PHENOMENEX.RTM. Luna Axia 5u C18 30.times.100 mm;

Flow rate: 20 mL/min;

Solvent A: 10% ACN, 90% water, 0.1% trifluoroacetic Acid; and

Solvent B: 90% ACN, 10% water, 0.1% trifluoroacetic Acid.

Preparative LC/MS (unless otherwise noted) with the following conditions:

Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B;

Column: Waters XBridge C18, 19.times.250 mm, 5-.mu.m particles;

Guard Column: Waters XBridge C18, 19.times.10 mm, 5-.mu.m particles;

Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;

Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;

Flow rate: 20 mL/min.

Analytical HPLC (unless otherwise noted) was performed to determine compound purity on a Shimadzu SIL-10A using the following method (Unless otherwise stated, retention times listed in Examples refer the retention times of Column 1):

Preparatory chiral SFC chromatography (unless otherwise noted) was performed on a Berger Multigram II SFC chromatograph using the following method:

UV visualization at 220 nm;

Column: Chiralpak AD-H SFC, 250.times.21 mm ID, 5 .mu.m;

Flow rate: 60.0 mL/min, 150 bar backpressure; and

Mobile Phase: 60/40, CO.sub.2/MeOH.

Analytical chiral SFC chromatography (unless otherwise noted) was performed on an Aurora Analytical SFC chromatography using the following method:

UV visualization at 220 nm;

Column: Chiralpak AD-H, 250.times.4.6 mm ID, 5 .mu.m;

Flow rate: 3 mL/min, 150 bar backpressure; and

Mobile Phase: 60/40, CO.sub.2/MeOH.

NMR Employed in Characterization of Examples

.sup.1H NMR spectra (unless otherwise noted) were obtained with JEOL or Bruker FOURIER.RTM. transform spectrometers operating at 400 MHz or 500 MHz. .sup.1H-nOe experiments were performed in some cases for regiochemistry elucidation with a 400
MHz Bruker FOURIER.RTM. Transform spectrometer.

Spectral data are reported as chemical shift (multiplicity, number of hydrogens, coupling constants in Hz) and are reported in ppm (.delta. units) relative to either an internal standard (tetramethyl silane=0 ppm) for .sup.1H NMR spectra, or
are referenced to the residual solvent peak (2.49 ppm for CD.sub.3SOCD.sub.2H, 3.30 ppm for CD.sub.2HOD, 1.94 for CHD.sub.2CN, 7.26 ppm for CHCl.sub.3, 5.32 ppm for CDHCl.sub.2).

1C N'-(4-Bromophenyl)-2,2,2-trifluoroacetohydrazide. To a stirred suspension of (4-bromophenyl)hydrazine hydrochloride (100 g, 447 mmol) in DCM (1500 mL) at rt was added dropwise a solution of TFAA (68.4 mL, 492 mmol) in DCM (150 mL). The
reaction mixture was stirred at rt for 2 h and TFAA (45 mL, 324 mmol) was added slowly to the reaction mixture. After 5 min, no more solids left and the reaction was judged complete by LCMS. The reaction mixture was concentrated to half volume, and the
mixture was diluted with hexane (.about.1 L), resulting in an off white crystalline precipitate. The mixture was filtered and the solids were rinsed with hexanes. The resulting solid was dried under high-vac 12 h at 50.degree. C. to give
N'-(4-bromophenyl)-2,2,2-trifluoroacetohydrazide (103 g, 364 mmol, 81% yield) as an off white crystalline compound. The mother liquor was concentrated and redissolved in DCM and 3 g N'-(4-bromophenyl)-2,2,2-trifluoroacetohydrazide was added. The
mixture was stirred for 20 min and hexane was added to give a suspension, which was filtrated and dried to give an additional 6.3 g (+4.96% yield) of N'-(4-bromophenyl)-2,2,2-trifluoroacetohydrazide as an off white crystalline compound. LCMS: RT=2.52
min (86.6%), m/z calc'd 282, 284, obs 305, 307 [M+Na]. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10 (br. s., 1H), 7.46-7.33 (m, 2H), 6.79-6.67 (m, 2H), 6.06 (br. s., 1H).

1D (Z)--N'-(4-Bromophenyl)-2,2,2-trifluoroacetohydrazonoyl chloride. To a solution of N'-(4-bromophenyl)-2,2,2-trifluoroacetohydrazide (111.3 g, 393 mmol) in EtOAc (1500 mL) at rt was added dropwise benzenesulfonyl chloride (53.8 mL, 413 mmol). The mixture was cooled to 0.degree. C. and Hunig's Base (72.8 mL, 413 mmol) was added dropwise. The resulting mixture was stirred at rt overnight, and the reaction was judged complete as monitored by LCMS. The mixture was diluted with EtOAc and the
organic layer was washed with water (3.times.2 L). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (Z)--N'-(4-bromophenyl)-2,2,2-trifluoroacetohydrazonoyl chloride (119 g, 393 mmol, 100% yield) as a yellow
liquid, which was used for next step without further purification. Analytical HPLC: RT=3.93 min (83.1%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (br. s., 1H), 7.51-7.36 (m, 2H), 7.11-6.94 (m, 2H).

1E (S,E)-3-But-2-enoyl-4-phenyloxazolidin-2-one. To a solution of (S)-(+)-4-phenyl-2-oxazolidinone (84.4 g, 517 mmol), lithium chloride (22.81 g, 538 mmol) and triethylamine (79 mL, 564 mmol) in THF (1200 mL) in a 5 L 3-neck flask at -5.degree. C. was added crotonic anhydride (76 mL, 512 mmol) over 5 min. The reaction temperature increased slightly during the addition. The mixture was allowed to warm to rt, resulting in a white milky solution. The reaction mixture was stirred at rt overnight. Upon completion, as monitored by LCMS, the reaction mixture was quenched with 0.2M aqueous HCl (600 mL) to give an aqueous layer of pH.about.7. The two layers were seperated and the aqueous layer was extracted with EtOAc (400 mL). The combined EtOAc
and THF layers were washed with brine, and dried over Na.sub.2SO.sub.4 and concentrated to give an light brown oil (200 mL). To the oil was added MeOH (200 mL). Crystals formed slowly at the beginning and then precipitated over 15 min. The product was
collected by filtration and rinsed with MeOH (200 mL) to give white solid. More product was collected from the MeOH filtrate, and the materials were combined and dried to give 101.6 g of (S,E)-3-But-2-enoyl-4-phenyloxazolidin-2-one as white crystals.

4C. 1-(5-chloro-2,3-dihydrobenzofuran-6-yl)piperidin-4-ol: To 1-(5-chloro-2,3-dihydrobenzofuran-6-yl)piperidin-4-one (38 mg, 0.15 mmol) in MeOH (1.2 mL) and THF (0.48 mL) at 0.degree. C., sodium borohydride (17 mg, 0.45 mmol) was added
portionwise. The reaction was stirred at 0.degree. C. for 10 min and at rt for 1 h. The reaction mixture was cooled with ice-water bath, quenched with 1 mL sat. NaHCO.sub.3. MeOH and THF were evaporated. The residue was extracted with EtOAc. The
extracts were washed with water, brine, dried (MgSO.sub.4) and concentrated to give 1-(5-chloro-2,3-dihydrobenzofuran-6-yl)piperidin-4-ol as a white solid (39 mg, 100% yield), which was used without further purification. LC-MS Anal. Calc'd for
C.sub.13H.sub.16ClNO.sub.2 253.09, found [M+H] 254.1.

13A. 1-(thiazol-2-yl)piperidin-4-ol: A mixture of piperidin-4-ol (154 mg, 1.52 mmol), 2-bromothiazole (250 mg, 1.524 mmol) and cesium carbonate (497 mg, 1.52 mmol) in toluene (1 mL) was heated at 95.degree. C. overnight. The reaction mixture
was concentrated to remove solvent, and then was diluted with EtOAc to which was then added aqueous NaHCO.sub.3. The organic layer was collected and was washed with H.sub.2O and then brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification via
silica gel chromatography gave the desired product as a yellow oil (140 mg, 50% yield). LC-MS Anal. Calc'd for C.sub.8H.sub.12N.sub.2OS, 184.07, found [M+H] 185.1.

16A. 1-(2,3-difluoro-5-methoxyphenyl)piperidin-4-ol: To 1,2,3-trifluoro-5-methoxybenzene (1 g, 6.17 mmol) was added piperidin-4-ol (1.87 g, 18.51 mmol) and DMSO (10 mL). The reaction was capped and placed in a 140.degree. C. oil bath for 3
hours. The reaction mixture was filtered and the solids rinsed into the filtrate with 2 mL of EtOAc. The filtrate was added to 50 mL of water and 50 mL of EtOAc, the mixture was well stirred, allowed to settle, and then the lower aqueous layer was
removed. The EtOAc layer was washed with an additional 3.times.50 mL of water. The EtOAc layer was passed through a 30 mm id.times.40 mm silica gel plug using a total of 200 mL of EtOAc. The filtrate was concentrated in vacuo to give the product as a
tan solid (1.02 g, 68% yield). LC-MS Anal. Calc'd for C.sub.12H.sub.15F.sub.2NO.sub.2 243.11, found [M+H] 244.1. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 6.33 (dd, J=5.8, 3.0 Hz, 1H), 6.27-6.17 (m, 1H), 3.97-3.80 (m, 1H), 3.75 (s, 3H), 3.53-3.19 (m,
2H), 3.02-2.78 (m, 2H), 2.04 (d, J=9.9 Hz, 2H), 1.84-1.69 (m, 2H), 1.61-1.40 (m, 1H).

16B. Methyl 2-((4S,5S)-1-(4-((1-(2,3-difluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phen- yl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of triphenylphosphine (107 mg, 0.407 mmol) and DMF (1 mL) was added
(E)-diethyl diazene-1,2-dicarboxylate (0.055 mL, 0.349 mmol) and the mixture was stirred at rt for 5 min. This mixture was added to the thick amber oil methyl 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1-
H-pyrazol-5-yl)acetate (1J, 92 mg, 0.291 mmol) and the mixture was stirred for 5 minutes. To this amber solution was added 1-(2,3-difluoro-5-methoxyphenyl)piperidin-4-ol (77 mg, 0.317 mmol) and the mixture was stirred for 5 hours. The reaction mixture
was quenched with 5 mL of water and 20 mL of EtOAc. The organic layer was washed with 3.times.5 mL of additional water and then the solvent from the organic layer was removed in vacuo. The residue was purified via silica gel chromatography to give the
desired product as a pale amber oil (39 mg, 24% yield). LC-MS Anal. Calc'd for C.sub.26H.sub.28F.sub.5N.sub.3O.sub.4 541.20, found [M+H] 542.2.

81B. 4-bromo-5-chloro-2-methoxypyridine: To MeOH (390 mL) was added chlorotrimethylsilane (49 mL, 386 mmol) at 0.degree. C., and the solution was warmed to rt and stirred for 30 min. To the resulting solution was added
4-bromo-5-chloropyridin-2-amine (20 g, 96 mmol), and the mixture was stirred for 15 min. To the reaction mixture was added sodium nitrite (2.7 g, 40 mmol) and the solution was stirred at 50.degree. C. for 3 h. The reaction mixture was evaporated in
vacuo, and the residue was diluted with EtOAc. The pH of the aqueous layer was adjusted to pH=.about.12 via addition of 1 N NaOH, and the solution was extracted 3.times. with EtOAc. The combined organic layers were concentrated, and the residue was
purified via recrystallization from MeOH and H.sub.2O to give 4-bromo-5-chloro-2-methoxypyridine as white crystalline needles (18 g, 81 mmol, 84% yield). LC-MS Anal. Calc'd for C.sub.6H.sub.5BrClNO, 220.92, found [M+H] 223.9. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.18 (s, 1H), 7.08 (s, 1H), 3.94 (s, 4H).

88B. 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetohydrazonoyl chloride: To a stirred solution of 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetohydrazide (6.48 g, 22.14 mmol) in EtOAc (120 mL) was added benzenesulfonyl chloride (3.44 mL, 26.6 mmol) at
rt. The solution was cooled to 0.degree. C., and to the solution was added N,N-diisopropylethylamine (5.80 mL, 33.2 mmol) dropwise. The resulting mixture was stirred at 0.degree. C. for 20 min, and then warmed to rt. After stirring at rt overnight,
the mixture was diluted with EtOAc and, washed with sat'd NaHCO.sub.3 and water. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated and the crude was purified via silica gel chromatography (0 to 10% EtOAc) to provide the desired product
(4.22 g, 75% yield) as a reddish liquid: LC-MS [M+H] 253, 255.

88C. (4S,5R)- and (4R,5S)-methyl 4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-5- -carboxylate: A stirred mixture of 2,2,2-trifluoro-N'-(4-methoxyphenyl)acetohydrazonoyl chloride (1.20 g, 4.51 mmol), (E)-methyl
pent-2-enoate (1.593 g, 13.54 mmol) and silver carbonate (2.489 g, 9.03 mmol) in dioxane (20 mL) was sonicated under vacuum and refilled with argon three times. The mixture was heated to 65.degree. C. and stirred at this temperature overnight. Then,
the mixture was filtered and the filter cake was rinsed with CH.sub.2Cl.sub.2. The combined filtrates were concentrated and purified via silica gel chromatography to afford the desired product (910 mg, 61.1% yield) as a reddish oil: LC-MS [M+H] 331.

88E. ((4S,5R)- and (4R,5S)-4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py- razol-5-yl)methyl methanesulfonate: To a stirred solution of ((4S,5R)- and (4R,5S)-4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py-
razol-5-yl)methanol (705 mg, 2.146 mmol) in CH.sub.2Cl.sub.2 (10.0 mL) at 0.degree. C. was added methanesulfonyl chloride (0.251 mL, 3.22 mmol) and then triethylamine (0.748 mL, 5.36 mmol). The resulting mixture was stirred overnight while allowing the
temperature to reach rt. The reaction mixture was diluted with CH.sub.2Cl.sub.2 and washed with sat'd NaHCO.sub.3 and water. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated and the crude was purified via silica gel chromatography to
give the desired product (678 mg, 83% yield) as a yellowish oil: LC-MS [M+H] 381.

88F. 2-((4S,5S) and (4R,5R)-4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py- razol-5-yl)acetonitrile: To a stirred solution of ((4S,5R)- and (4R,5S)-4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py-
razol-5-yl)methyl methanesulfonate (678 mg, 1.782 mmol) was added potassium cyanide (239 mg, 3.56 mmol). The resulting mixture was heated to 50.degree. C. and stirred at this temperature for 19 h. After this time, the reaction mixture was cooled to rt,
diluted with sat.NaHCO.sub.3 and extracted with EtOAc. The organic extract was washed with sat'd NaCl, dried (Na.sub.2SO.sub.4) and concentrated. Purification via silica gel chromatography afforded the desired product (512 mg, 91% yield) as an orangish
oil: LC-MS [M+H] 312.

88G. 2-((4S,5S)- and (4R,4S)-4-ethyl-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py- razol-5-yl)acetonitrile: To a stirred solution of 2-((4S,5S) and (4R,5R)-4-ethyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py-
razol-5-yl)acetonitrile (512 mg, 1.628 mmol) in CH.sub.2Cl.sub.2 (4.0 mL) at -78.degree. C. under argon was added boron tribromide (0.308 mL, 3.26 mmol) dropwise. The resulting mixture was stirred at -78.degree. C. for 10 min, then allowed to warm up
to 0.degree. C. and stirred for 1 h. At this time, the reaction mixture was quenched with MeOH (20 mL), allowed to warm up to rt and stirred for 1 h. The mixture was concentrated and the crude was purified via silica gel chromatography to provide the
desired product (427 mg, 82% yield) as a yellowish solid: LC-MS [M+H] 298.

88H. 1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl4-methylbenzenesulfonate: To a stirred solution of 1-(2-fluoro-5-methoxyphenyl)piperidin-4-ol (1.25 g, 5.55 mmol) in CH.sub.2Cl.sub.2 (25 mL) at rt was added 4-methylbenzene-1-sulfonyl chloride
(1.270 g, 6.66 mmol) followed by pyridine (2.244 mL, 27.7 mmol). The resulting mixture was stirred at rt overnight and then washed with water. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated, and the crude was purified via silica gel
chromatography to give the desired product (1.38 g, 65.5% yield) as a white solid: LC-MS [M+H] 380.

88I. 2-((4S,5S)- and (4R,5R)-4-ethyl-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phe- nyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile: To a stirred mixture of
1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl4-methylbenzenesulfonate (390 mg, 1.0 mmol) and 2-((4S,5S)- and (4R,5R)-4-ethyl-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-py- razol-5-yl)acetonitrile (430 mg, 1.4 mmol) in DMF (10 mL) was added
cesium carbonate (1.0 g, 3.1 mmol). The resulting mixture was heated to 50.degree. C. and stirred at this temperature overnight. Then, the mixture was diluted with water and extracted with EtOAc. The organic extract was dried (Na.sub.2SO.sub.4) and
concentrated, and the crude was purified via silica gel chromatography to afford the desired product (206 mg, 36.5% yield) as a yellowish oil: LC-MS [M+H] 505.

88J. methyl 2-((4S,5S)- and (4R,5R)-4-ethyl-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phe- nyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: 2-(4S,5S)- and
(4R,5R)-4-ethyl-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy- )phenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile was dissolved in .about.3M HCl/MeOH, MeOAc solution [6.85 mL, prepared by addition of AcCl (1.45 mL) to MeOH (5.4
mL) at 0.degree. C. and then stirring at rt for 30 min]. The resulting solution was allowed to stand at rt for 3.5 days and then evaporated. Purification via silica gel chromatography provided the desired product (102 mg, 46.5% yield) as a colorless
oil: LC-MS [M+H] 538.

90A. (E)-benzyl 4-cyclopropylbut-2-enoate: To a stirred solution of sodium hydride (0.7 g, 18 mmol) in THF (20 mL) at 0.degree. C. under argon was added a solution of benzyl 2-(dimethoxyphosphoryl)acetate (3.8 g, 14 mmol) in THF (5.0 mL),
slowly. The mixture was stirred at 0.degree. C. for 15 min until it turned into a clear solution and then, a solution of 2-cyclopropylacetaldehyde (1.0 g, 12 mmol) in THF (5.0 mL) was added dropwise. The resulting mixture was allowed to warm up to rt
and was stirred at rt for 6 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic extract was dried (Na.sub.2SO.sub.4) and concentrated and the crude was purified via silica gel chromatography to provide the desired
product (1.3 g, 44% yield) as a colorless oil: LC-MS [M+Na] 239.

91A. 4-((2-(4-methoxyphenyl)hydrazono)methyl)benzonitrile: To a solution of 4-methoxyphenylhydrazine hydrochloride (626 mg, 3.51 mmol) and 4-cyanobenzaldehyde (421 mg, 3.21 mmol) in DMF (3.5 mL) was added triethylamine (1.0 mL, 7.14 mmol). The
mixture was stirred at rt under Ar for 47 h, water (6.8 mL) was added and stirring was continued for 1 h. The solid that resulted was filtered, rinsed with water (6 mL) and dissolved in CH.sub.2Cl.sub.2 (100 mL). The CH.sub.2Cl.sub.2 solution was dried
(Na.sub.2SO.sub.4, overnight) and concentrated to provide the desired product (857 mg, 97% yield) as a brownish solid: LC-MS [M+H] 252.

91C. 4-((4S,5R)-1-(4-methoxyphenyl)-4-methyl-5-((S)-2-oxo-4-phenyloxazoli- dine-3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile and 4-((4R,5S)-1-(4-methoxyphenyl)-4-methyl-5-((S)-2-oxo-4-phenyloxazolidine--
3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile: A flask containing a solution of 4-cyano-N'-(4-methoxyphenyl)benzohydrazonoyl bromide (416 mg, 1.121 mmol) and (S,E)-3-(but-2-enoyl)-4-phenyloxazolidin-2-one (300 mg, 1.271 mmol) in dioxane (16 mL)
was evacuated and backfilled with Ar. Silver carbonate (877 mg, 3.15 mmol) was added to the solution and the resulting suspension was stirred and heated to 50.degree. C. After stirring at this temperature for 14.5 h, the reaction mixture was cooled to
rt and filtered through Celite. The filter cake was rinsed with EtOAc (120 mL) and, the combined filtrate and rinse were concentrated. The crude was chromatographed to afford 4-((4S,5R)-1-(4-methoxyphenyl)-4-methyl-5-((S)-2-oxo-4-phenyloxazolidine--
3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (152 mg, 28% yield) as a yellow solid: LC-MS [M+H] 481. Further elution of the silica column gave a mixture of the diastereomers (270 mg, 50% yield) followed by
4-((4R,5S)-1-(4-methoxyphenyl)-4-methyl-5-((S)-2-oxo-4-phenyloxazolidine-- 3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (18 mg, 3% yield) as a yellow solid: LC-MS [M+H] 481.

91D. 4-((4S,5R)-5-(hydroxymethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydr- o-1H-pyrazol-3-yl)benzonitrile: To a solution of 4-((4S,5R)-1-(4-methoxyphenyl)-4-methyl-5-((S)-2-oxo-4-phenyloxazolidine--
3-carbonyl)-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (171 mg, 0.356 mmol) in THF (6.0 mL) at rt was added a solution of sodium borohydride (83 mg, 2.172 mmol) in water (1.2 mL). After stirring at rt for 4.4 h, the reaction mixture was cooled to
0.degree. C. and quenched with 10% KHSO.sub.4 (10 mL). The resulting aqueous mixture was allowed to warm up to rt and stirred for 2 h. The organic solvent was mostly evaporated under reduced pressure and the remaining aqueous mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated. Chromatography of the crude afforded the desired product (138 mg, 99% yield) as a yellow oil: LC-MS [M+H] 322.

91G. 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-- 1H-pyrazol-3-yl)benzonitrile: To a solution of 4-((4S,5S)-5-(cyanomethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (93 mg, 0.28 mmol) in
CH.sub.2Cl.sub.2 (0.8 mL) at 0.degree. C. was added boron trifluoride-methyl sulfide complex (0.18 mL, 1.7 mmol). The reaction mixture was stirred at 0.degree. C. for 20 min and then at rt for 2.7 h. The reaction mixture was cooled to 0.degree. C.
and the reaction was quenched with MeOH (6.0 mL) followed by AcCl (0.2 mL). The mixture was allowed to warm up to rt, stirred for 1.5 h and evaporated. The residue was taken up in EtOAc (50 mL) and, washed with 5% NaHCO.sub.3 (2.times.25 mL) and sat'd
NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. Purification via silica gel chromatography provided the desired product (87 mg, 97% yield) as a yellow oil: LCMS [M+H] 317.

94A. 4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-- 1H-pyrazol-3-yl)-3-fluorobenzonitrile was prepared from 3-fluoro-4-formylbenzonitrile following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H- -pyrazol-3-yl)benzonitrile (91G): LC-MS [M+H] 335.

95A. 2-((4S,5S)-1-(4-bromophenyl)-3-(4-fluorophenyl)-4-methyl-4,5-dihydro- -1H-pyrazol-5-yl)acetonitrile was prepared from 4-fluorobenzaldehyde and (4-bromophenyl)hydrazine following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (example 91G). LC-MS [M+H] 372, 374.

96A. 4-((4S,5S)-1-(4-bromophenyl)-5-(cyanomethyl)-4-methyl-4,5-dihydro-1H- -pyrazol-3-yl)phthalonitrile was prepared from 2-fluoro-5-formylbenzonitrile and (4-bromophenyl)hydrazine following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (example 91G) but 3 equivalents of potassium cyanide were used in the last step. LC-MS [M+H] 404, 406.

97A. 2-((4R,5R)-1-(4-bromophenyl)-3-(3,4-difluorophenyl)-4-methyl-4,5-dih- ydro-1H-pyrazol-5-yl)acetonitrile was prepared from 3,4-difluorobenzaldehyde and (4-bromophenyl)hydrazine following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (example 90G). LC-MS [M+H] 390, 392.

97B. 2-((4R,5R)-3-(3,4-difluorophenyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-d- ihydro-1H-pyrazol-5-yl)acetonitrile was prepared from 2-((4R,5R)-1-(4-bromophenyl)-3-(3,4-difluorophenyl)-4-methyl-4,5-dihydro-- 1H-pyrazol-5-yl)acetonitrile following
the procedure for the preparation of 2-((4S,5S)-3-(4-fluorophenyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro- -1H-pyrazol-5-yl)acetonitrile (example 95B). LC-MS [M+H] 328.

98A. 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(4-(methylsulfonyl)phenyl)- -4,5-dihydro-1H-pyrazol-5-yl)acetonitrile was prepared from 4-(methylsulfonyl)benzaldehyde following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (example 91G): LC-MS [M+H] 370.

99A. (E)-pent-2-enoic anhydride: To a stirred solution of (E)-pent-2-enoic acid (5 g, 48.9 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added triethylamine (6.82 mL, 48.9 mmol). The resulting solution was purged with argon and then cooled to
0.degree. C. Triphosgene (2.90 g, 9.79 mmol) was slowly added in portions and after completion of the addition, the resulting mixture was allowed to warm up to rt and stirred under argon overnight. The solvent was removed by blowing nitrogen onto the
reaction mixture and the residual white solid was taken up in EtOAc (20 mL). The resulting suspension was filtered and the filter cake was rinsed with Et.sub.2O. The combined filtrates were concentrated to afford the desired product (5.10 g,
quantitative yield) as an orange liquid: LC-MS [M+Na] 205.

99B. (S,E)-3-(pent-2-enoyl)-4-phenyloxazolidin-2-one: To a light suspension of (S)-4-phenyloxazolidin-2-one (3.8 g, 23 mmol), lithium chloride (1.017 g, 24 mmol) and triethylamine (4.32 mL, 31 mmol) in THF (50 mL) at -20.degree. C. was added
(E)-pent-2-enoic anhydride (5.09 g, 27.9 mmol) dropwise. After completion of addition, the cold bath was removed and the mixture was allowed to warm to rt. The mixture was stirred at rt for 2.5 days and the resulting thick suspension was diluted with
EtOAc. The mixture was washed sequentially with 0.2M HCl, sat'd NaHCO.sub.3, water and sat'd NaCl. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give an orange liquid which was purified via silica gel chromatography to afford (the
desired product (4.37 g, 76% yield) as a white solid: LC-MS [M+H] 246.

99C. 4-((4S,5S)-5-(cyanomethyl)-4-ethyl-1-(4-hydroxyphenyl)-4,5-dihydro-1- H-pyrazol-3-yl)benzonitrile was prepared from (S,E)-3-(pent-2-enoyl)-4-phenyloxazolidin-2-one following the procedure for the preparation of
4-((4S,5S)-5-(cyanomethyl)-1-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-py- razol-3-yl)benzonitrile (example 91G): LC-MS [M+H] 331.

100B. 1-(2-fluoro-5-methoxyphenyl)piperidin-4-one: To a stirred solution of 8-(2-fluoro-5-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (541 mg, 2.024 mmol) in THF (2.0 mL) at rt was added 1.78M sulfuric acid (5.7 mL, 10.15 mmol) and the
resulting solution was heated to 66.degree. C. After stirring at this temperature for 11 h, the reaction mixture was cooled to 0.degree. C. and then quenched by dropwise addition of sat'd NaHCO.sub.3 (10 mL) followed by excess sat'd NaHCO.sub.3 (30
mL). The mixture was stirred for 15 min and then extracted with CH.sub.2Cl.sub.2 (3.times.30 mL). The organic extracts were washed with sat'd NaCl (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification via silica gel chromatography of the
crude gave the desired product (352 mg, 1.42 mmol, 70% yield) as a colorless oil: LC-MS [M+H] 224.

100C. 1-(2-fluoro-5-methoxyphenyl)-4-methylenepiperidine: To a suspension of methyltriphenylphosphonium iodide (970 mg, 2.352 mmol) in THF (9.7 mL) at 0.degree. C. was added 2.5M butyl lithium/toluene (0.94 mL, 2.350 mmol) and the mixture was
stirred at 0.degree. C. for 30 min. A solution 1-(2-fluoro-5-methoxyphenyl)piperidin-4-one (434 mg, 1.750 mmol) in THF (2.4 mL) was added dropwise, and the resulting suspension was allowed to warm to rt over 3.0 h. The rxn was quenched with sat'd
NH.sub.4Cl (20 mL) and diluted with EtOAc (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2.times.20 mL). The combined organic layers were washed with sat'd NaCl (20 mL), dried (Na.sub.2SO.sub.4) and evaporated. The
crude was chromatographed to afford the desired product (269 mg, 1.118 mmol, 63.9% yield) as a colorless oil: LC-MS [M+H] 222.

100D. 2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl- )phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonit- rile: 0.5M 9-Borabicyclo[3.3.1]nonane/THF (1.3 mL, 0.650 mmol) was added to a solution of
1-(2-fluoro-5-methoxyphenyl)-4-methylenepiperidine (118 mg, 0.491 mmol) in THF (1.5 mL) and the resulting solution was heated at 65.degree. C. for 1.5 h. After cooling to rt, the solution was added to a vigorously stirred mixture of
2-((4S,5S)-1-(4-bromophenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-- pyrazol-5-yl)acetonitrile (191 mg, 0.546 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (22 mg, 0.027 mmol), DMF (1.9 mL), water
(0.2 mL) and potassium carbonate (153 mg, 1.107 mmol) under Ar. The mixture was heated to 65.degree. C. and stirred at this temperature for 3.5 h, cooled to rt and poured onto water (40 mL). The pH of the resulting aqueous mixture was adjusted to 11
by addition of 1M NaOH and the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.40 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated. Purification by two consecutive chromatographies (SiO.sub.2, first 4/1 to 7/3
Hex/EtOAc and then CHCl.sub.3 to 97/3 CHCl.sub.3/Ether) gave the desired product (31 mg, 11% yield) as a colorless oil: LC-MS [M+H] 489.

100E. methyl 2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)pheny- l)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: 2-((4S,5S)-1-(4-((1-(2-Fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)pheny-
l)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (27 mg, 0.054 mmol) was dissolved in .about.3M HCl/MeOH, CH.sub.2Cl.sub.2, MeOAc solution [6.3 mL, prepared by addition of AcCl (1.3 mL) to a 3/2 CHCl.sub.2/MeOH solution (5.0 mL)
at 0.degree. C. and then stirring at rt for 20 min]. The resulting solution was allowed to stand at rt for 15 h and then evaporated. The remaining oily material was stripped from MeOH (2.times.4 mL) and dissolved in .about.3M HCl/MeOH, MeOAc solution
[6.3 mL, prepared by addition of AcCl (1.3 mL) to MeOH (5 mL) at 0.degree. C. and then stirring at rt for 30 min]. The resulting solution was heated to 38.degree. C. and allowed to stand at this temperature for 22 h. At this time, the solution was
cooled to rt, diluted with MeCN (5 mL) and evaporated. The residue was taken up in EtOAc (50 mL) and, washed with 5% NaHCO.sub.3 (2.times.30 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was
chromatographed (SiO.sub.2, 4/1 Hex/EtOAc) to afford the desired product (26 mg, 91% yield) as a colorless oil: LC-MS [M+H] 522.

102A. ethyl 2-((4S,5S)-1-(4-((1-(2-fluoro-5-hydroxyphenyl)piperidin-4-yl)oxy)phenyl)-- 4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of EtOH (0.86 mL) was added acetyl chloride (0.18 mL, 2.6 mmol) to generate
anhydrous HCl. After addition, the mixture was warmed to room temp, and 2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)ox- y)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (Example 1, 0.044 g, 0.086 mmol) was
added. The mixture was stirred at rt for 1.5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in CH.sub.2Cl.sub.2 (0.6 mL) and was cooled to -78.degree. C., and BBr.sub.3 (0.8 mL, 8.46 mmol) was added. The reaction mixture
was stirred for 2h, and was warmed to -40.degree. C. overnight. The reaction solution was poured over ice and, after 30 min agitation, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO.sub.4,
filtered and evaporated to give 85 mg of a yellow oil that was purified via silica chromatography to give 25 mg of desired product as a clear oil. Anal. Calc'd for C.sub.26H.sub.29F.sub.4N.sub.3O.sub.4: 523.21, LCMS obs. [M+H]=524.1.

A1G. 1-(5-Chloro-2-methoxypyridin-4-yl)-3-fluoropiperidin-4-ol: To a mixture of 4-(4-((tert-butyldimethylsilyl)oxy)-3-fluoropiperidin-1-yl)-5-chloro-2-me- thoxypyridine (192 mg, 0.51 mmol) in THF (1.0 mL) was added TBAF (0.6 mL, 0.61 mmol).
The reaction mixture was stirred at 23.degree. C. for 2 h and sat. aq NaHCO.sub.3 (10 mL) was added slowly to the reaction mixture. The mixture was then extracted with EtOAc (2.times.10 mL), and the combined organic extracts were washed with water (20
mL) and brine (20 mL), and dried (Na.sub.2SO.sub.4), filtered, and concentrated. Purification by chromatography gave the title compound (110 mg, 0.42 mmol, 82% yield) as a white foam. LC-MS Anal. Calc'd for C.sub.11H.sub.24ClFN.sub.2O.sub.2 260.07,
found [M+H] 261.0.

A3B. (4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methyl-1-(4-(4,4,- 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)-4,5-di- hydro-1H-pyrazole: A flask containing a suspension of
(4S,5R)-1-(4-bromophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-meth- yl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazole (351 mg, 0.778 mmol), bis(pinacolato)diboron (230 mg, 0.897 mmol) and potassium acetate (232 mg, 2.340 mmol) in DMF (1.4 mL) was
evacuated and backfilled with Ar. [1,1-bis(Diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (32 mg, 0.039 mmol) was added to the suspension and the mixture was degassed by ultrasound irradiation under Ar for 5 min. The
mixture was heated to 80.degree. C. and stirred at this temperature for 6 h. At this time, the reaction mixture was allowed to cool to rt while stirring for an additional 12 h. The reaction mixture was filtered through Celite and the filter cake was
rinsed with EtOAc (80 mL). The combined filtrate and rinse were washed with 10% Na.sub.2CO.sub.3 (2.times.40 mL), water (40 mL) and sat'd NaCl (40 mL), dried (Na.sub.2SO.sub.4) and evaporated. To a solution of the residue and imidazole (116 mg, 1.69
mmol) in CH.sub.2Cl.sub.2 (2.1 mL) at rt was added a solution of tert-butyldimethylsilyl chloride (132 mg, 0.85 mmol) in CH.sub.2Cl.sub.2 (1.1 mL) dropwise. The reaction mixture was stirred at rt for 14 h and then, diluted with EtOAc (80 mL) and washed
with sat'd NaHCO.sub.3 (2.times.40 mL) and sat'd NaCl (40 mL). The organic layer was dried (Na.sub.2SO.sub.4) and evaporated. The crude was chromatographed (SiO.sub.2, 95/5 to 9/1 Hex/Ether) to provide
(4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methyl-1-(4-(4,4,5,5-t- etramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)-4,5-dihydro- -1H-pyrazole (318 mg, 82% yield) as a colorless oil: LC-MS [M+H] 499.

A3D. 3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl- -3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenol: To a stirred solution of 4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoro-
methyl)-4,5-dihydro-1H-pyrazol-1-yl)phenol (44.5 mg, 0.115 mmol) in CH.sub.2Cl.sub.2 (2.3 mL) at 0.degree. C. was added pyridinium bromide perbromide (41 mg, 0.115 mmol) in three portions. The solution turned purple after portion addition and was
stirred, until it turned back to clear, before addition of the next portion. After addition of the last portion, the reaction mixture was stirred until decoloration and then quenched with 10% Na.sub.2S.sub.2O.sub.3 (4.0 mL). The aqueous mixture was
allowed to warm to rt and stirred for 30 min. The final mixture was partitioned between EtOAc (50 mL) and water (10 mL). The organic layer was washed with 5% NaHCO.sub.3 (2.times.30 mL) and sat'd NaCl (20 mL), dried (Na.sub.2SO.sub.4) and evaporated.
To a solution of the residue in CH.sub.2Cl.sub.2 (0.5 mL) at rt was added a solution of tert-butyldimethylsilyl chloride (32 mg, 0.206 mmol) in CH.sub.2Cl.sub.2 (0.25 mL), dropwise. The reaction mixture was stirred at rt for 7.3 h. At this time,
additional imidazole (28 mg, 0.407 mmol) and solution of tert-butyldimethylsilyl chloride (32 mg, 0.206 mmol) in dichloromethane (0.25 mL) were added and stirring at rt was continued for an additional 11 h. The mixture was diluted with EtOAc (50 mL) and
washed with sat'd NaHCO.sub.3 (2.times.20 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and evaporated. To a solution of the resulting residue in DMF (0.45 mL) was added water (0.05 mL) followed by cesium carbonate (30 mg,
0.092 mmol). The resulting yellow solution was stirred at rt for 26 h. After this time, the solution was diluted with ether (40 mL) and washed with sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and evaporated, and the crude was
chromatographed (SiO.sub.2, 4/1Hex/EtOAc) to give a mixture of isomeric aryl bromides (30 mg). This isomeric mixture was separated by chromatography (SiO.sub.2, 96/4 CHCl.sub.3/Ether) to afford
3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(t- rifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenol (11 mg, 14.21% yield) as a colorless oil: LC-MS [M+H] 467, 469.

A3F. ((4S,5R)-1-(2-Bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3- -methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro- -1H-pyrazol-5-yl)methanol:
4-((3R,4R)-4-(3-Bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)- -4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenoxy)-3-methy- lpiperidin-1-yl)-5-chloro-2-methoxypyridine was dissolved in in .about.1.1M HCl/MeOH, MeOAc solution
[3.25 mL, prepared by addition of AcCl (0.25 mL) to MeOH (3.0 mL) at 0.degree. C. and then stirring at rt for 30 min]. The resulting solution was allowed to stand at rt for 12 h. After this time, the solution was diluted with MeCN (4 mL) and
evaporated. The residue was taken up in EtOAc (40 mL) and, washed with 5% NaHCO.sub.3 (2.times.20 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. Chromatography (SiO.sub.2, 4/1 to 7/3 Hex/EtOAc) of the
crude afforded ((4S,5R)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-meth- ylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-p- yrazol-5-yl)methanol (9 mg, 82% yield) as a colorless oil: LC-MS [M+H] 591, 593.

A3H. 2-((4S,5S)-1-(2-Bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)- -3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihyd- ro-1H-pyrazol-5-yl)acetonitrile: To a solution of
((4S,5R)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-meth- ylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-p- yrazol-5-yl)methyl methanesulfonate (10 mg, 0.015 mmol) in DMSO (0.2 mL) was added potassium cyanide
(2.0 mg, 0.030 mmol). The mixture was heated to 40.degree. C. and stirred at this temperature under Ar for 8.5 h. At this time, the mixture was cooled to rt and stirred for an additional 12 h. The mixture was diluted with EtOAc (40 mL) and, washed with
sat'd NaHCO.sub.3 (2.times.15 mL), water (2.times.15 mL) and sat'd NaCl (10 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was chromatographed (SiO.sub.2, 7/3 Hex/EtOAc) to give
2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetonitrile (7 mg, 78% yield) as a colorless oil: LC-MS [M+H] 600, 602.

A3I. Methyl 2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetate:
2-((4S,5S)-1-(2-Bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetonitrile (7 mg, 0.012 mmol) was dissolved in .about.3M HCl/MeOH, CH.sub.2Cl.sub.2,
MeOAc solution [3.8 mL, prepared by addition of AcCl (0.8 mL) to a 3/2 CH.sub.2Cl.sub.2/MeOH solution (3.0 mL) at 0.degree. C. and then stirring at rt for 20 min]. The resulting solution was allowed to stand at rt for 29 h. After this time, the
solution was evaporated and the remaining oily material was stripped from MeOH (2.times.4 mL). The residue was dissolved in .about.3M HCl/MeOH, MeOAc solution [3.8 mL, prepared by addition of AcCl (0.8 mL) to MeOH (3.0 mL) at 0.degree. C. and then
stirring at rt for 30 min] The resulting solution was heated to 40.degree. C. and allowed to stand at this temperature for 23 h. After this time, the solution was cooled to rt, diluted with MeCN (4 mL) and evaporated. The residue was taken up in EtOAc
(40 mL) and, washed with sat'd NaHCO.sub.3 (2.times.35 mL) and sat'd NaCl (30 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was chromatographed (SiO.sub.2, 4/1 Hex/EtOAc) to afford methyl
2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetate (7 mg, 89% yield) as a colorless oil: LC-MS [M+H] 633, 635.

A4A. 2-((4S,5S)-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y- l)phenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile: A flask containing a suspension of
2-((4S,5S)-1-(4-bromophenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-- pyrazol-5-yl)acetonitrile (1I, 645 mg, 1.863 mmol), bis(pinacolato)diboron (560 mg, 2.183 mmol) and potassium acetate (573 mg, 5.78 mmol) in DMF (3.4 mL) was evacuated and
backfilled with Ar. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (76 mg, 0.093 mmol) was added to the suspension and the mixture was degassed by ultrasound irradiation under Ar for 5 min. The mixture was
heated to 78.degree. C. and stirred at this temperature for 10.8 h. After this time, the reaction mixture was filtered through Celite and the filter cake was rinsed with EtOAc (130 mL). The combined filtrate and rinse were washed with 10%
Na.sub.2CO.sub.3 (50 mL), sat'd NaHCO.sub.3 (70 ml), water (70 mL) and sat'd NaCl (50 mL). The organic layer was dried (Na.sub.2SO.sub.4) and evaporated. The crude was chromatographed (SiO.sub.2, 4/1 to 7/3 Hex/EtOAc) to provide
2-((4S,5S)-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe- nyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (642 mg, 88% yield) as a colorless oil: LC-MS [M+H] 394.

A4B. 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihy- dro-1H-pyrazol-5-yl)acetonitrile: To a stirred solution of the 2-((4S,5S)-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (572 mg, 1.455 mmol) in EtOAc (6.4 mL) at rt was added 30% hydrogen peroxide (2.3 mL, 22.52 mmol) dropwise. The reaction mixture was stirred at rt for 22 h. After this time, the mixture
was cooled to 0.degree. C. and treated with 10% Na.sub.2S.sub.2O.sub.3 (35 mL). The resulting aqueous mixture was stirred at rt for 2 h and then extracted with EtOAc (3.times.50 mL). The organic extracts were washed with sat'd NaCl (40 mL), dried
(Na.sub.2SO.sub.4) and concentrated. Chromatography (SiO.sub.2, 3/2 Hex/EtOAc) of the crude afforded 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1- H-pyrazol-5-yl)acetonitrile (391 mg, 94% yield) as a yellowish oil: LC-MS
[M+H] 284.

A4D. Methyl 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetate:
2-((4S,5S)-1-(3-Bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetonitrile (258 mg, 0.425 mmol) was dissolved in .about.3M HCl/MeOH, CH.sub.2Cl.sub.2,
MeOAc solution [12.6 mL, prepared by addition of AcCl (2.6 mL) to a 3/2 CH.sub.2Cl.sub.2/MeOH solution (10.0 mL) at 0.degree. C. and then stirring at rt for 20 min]. The resulting solution was allowed to stand at rt for 18 h. The solution was
evaporated and the remaining oily material was stripped from MeOH (2.times.10 mL). The residue was dissolved in .about.3M HCl/MeOH, MeOAc solution [12.6 mL, prepared by addition of AcCl (2.6 mL) to MeOH (10.0 mL) at 0.degree. C. and then stirring at rt
for 30 min]. The resulting solution was heated to 40.degree. C. and allowed to stand at this temperature. for 23.0 h. After this time, the solution was cooled to rt, diluted with MeCN (10 mL) and evaporated. The residue was taken up in EtOAc (60 mL)
and, washed with sat'd NaHCO.sub.3 (2.times.35 mL) and sat'd NaCl (30 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was chromatographed (SiO.sub.2, 4/1 Hex/EtOAc) to afford methyl
2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me- thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetate: 2-((4S,5S)-1-(3-Bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-me-
thylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-5-yl)acetonitrile (247 mg, 92% yield) as a white solid: LC-MS [M+H] 633, 635.

B4B. Methyl 4-((4S,5S)-1-(4-((1-(5-ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-5- -(2-methoxy-2-oxoethyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)-3-fluorobenz- oate: B4A (7 mg, 0.012 mmol) was dissolved in .about.3M HCl/MeOH,
CH.sub.2Cl.sub.2, MeOAc solution [6.3 mL, prepared by addition of AcCl (1.3 mL) to a 3/2 CHCl.sub.2/MeOH solution (5.0 mL) at 0.degree. C. and then stirring at rt for 30 min]. The resulting solution was allowed to stand at rt for 25 h and then
evaporated. The remaining oily material was stripped from MeOH (2.times.4 mL) and dissolved in .about.3M HCl/MeOH, MeOAc solution [6.3 mL, prepared by addition of AcCl (1.3 mL) to MeOH (5 mL) at 0.degree. C. and then stirring at rt for 30 min]. The
resulting solution was heated to 40.degree. C. and allowed to stand at this temperature for 23.5 h. At this time, the solution was cooled to rt, diluted with MeCN (4 mL) and evaporated. The residue was taken up in EtOAc (40 mL) and, washed with sat'd
NaHCO.sub.3 (2.times.20 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was chromatographed (SiO.sub.2, 9/1 to 4/1 Hex/EtOAc) to afford the title compound (5.5 mg, 76% yield) as a yellow oil: LC-MS
[M+H] 622.

B5A. (4-Bromophenyl)carbonocyanidohydrazonic chloride: A solution of sodium nitrite (3.53 g, 49.6 mmol) in water (21.9 mL) was added to a stirred mixture of 4-bromoaniline (8.35 g, 47.1 mmol), hydrochloric acid, 37% (14.6 mL) and water (36.5
mL) cooled at -5.degree. C. The resulting mixture was stirred for 25 min while warming up to 0.degree. C. and then, 2-chloro-3-oxobutanenitrile (6.34 g, 53.9 mmol, was prepared as described in WO2007122241), EtOH (36.5 mL), sodium acetate (11.7 g, 141
mmol) and water (146 mL) were added in this order. The reaction mixture was allowed to warm up to rt and stirred for an additional 8.5 h. After this time, the mixture was filtered and the collected solid was thoroughly rinsed with water. The solid was
dried by suction followed by storage under vacuum. The solid was kept under vacuum for 48 h to give the desired product (8.76 g, 66.2% yield) as a brownish solid: LC-MS [M+H] 258, 260.

B5B. Methyl 1-(4-bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate: A flask containing a solution of (4-bromophenyl) carbonocyanidohydrazonic chloride (753 mg, 2.68 mmol) in dioxane (13.0 mL) was evacuated and backfilled with
Ar. Methyl crotonate (0.48 mL, 4.44 mmol) and silver carbonate (1780 mg, 6.39 mmol) were added to the solution and the resulting suspension was degassed by ultrasound irradiation under Ar for 5 min. The reaction mixture heated to 43.degree. C. and
stirred at this temperature for 14 h. After this time, the reaction was cooled to rt and filtered through Celite. The filter cake was rinsed with EtOAc (100 mL) and, the combined filtrate and rinse were concentrated. The crude was chromatographed
(SiO.sub.2, 4/1 Hex/EtOAc) to afford the desired product (837 mg, 81% yield) as a yellowish oil: LC-MS [M+H] 320, 322.

B5C. 1-(4-Bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazole-5-carboxy- lic acid: To a stirred solution of methyl 1-(4-bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (837 mg, 2.60 mmol) in THF (40 mL) and water (4.0 mL)
at rt was added 1M aqueous lithium hydroxide (5.7 mL, 5.70 mmol). After stirring at rt for 3.5 h, most of the THF was evaporated and the remaining mixture was partitioned between water (90 mL) and Hex (40 mL). The aqueous layer was acidified to pH 2 by
dropwise addition of 1M HCl, and then extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated. The crude was passed through a SiO.sub.2 column eluting with 9/1 CH.sub.2Cl.sub.2/MeOH
to give the title compound (657 mg, 70.3% yield) as a yellowish oil: LC-MS [M+H] 306, 308.

B5D. Methyl 2-(1-(4-bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazol-5-yl)acetate- : To a stirred solution of 1-(4-bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (657 mg, 1.535 mmol) in CH.sub.2Cl.sub.2 (6.5 mL) at
0.degree. C. were added 2M oxalyl chloride/CH.sub.2Cl.sub.2 (1.64 mL, 3.28 mmol) and DMF (3 drops). The reaction mixture was stirred at 0.degree. C. for 15 min and then, at rt for 1.5 h. The final mixture was evaporated in vacuo and the residue was
stripped from CH.sub.2Cl.sub.2 (2.times.10 mL) to give the crude acyl chloride. 2M Trimethylsilyldiazomethane/Ether (3.1 mL, 6.20 mmol) was added dropwise to a solution of the above crude acyl chloride in MeCN (6.0 mL) and THF (6.0 mL) at 0.degree. C.
under Ar. The mixture was stirred for 4.0 h, while slowly warming up to 6.degree. C., and then for 1.8 h at rt. At this time, the mixture was evaporated in vacuo to provide the crude diazoketone. To a solution of the crude diazoketone in MeOH (25.0
mL) under Ar was added a solution of silver benzoate (126 mg, 0.545 mmol) in triethylamine (1.52 mL, 10.85 mmol), over 5 min while the mixture was sonicated in an ultrasound bath. After sonicating for 2.0 h at rt, the resulting mixture was stirred at rt
overnight. The mixture was filtered through Celite and the filter cake was rinsed with EtOAc (100 mL). The filtrate and rinse were combined and evaporated to about 5 mL volume. The residue was taken up in EtOAc (100 mL) and washed with sat'd
NaHCO.sub.3 (70 mL), water (50 mL), 0.5M HCl (2.times.25 mL), water (50 mL) and sat'd NaCl (30 mL), dried (Na.sub.2SO.sub.4) and concentrated. The crude was chromatographed (SiO.sub.2, 4/1 Hex/EtOAc) to give the desired methyl ester contaminated with
starting acid methyl ester. The esters were separated by RF-HPLC (MeOH--H.sub.2O-TFA). Fractions containing the desired ester were combined, basified with solid NaHCO.sub.3 and partially evaporated at rt to remove most of the MeOH. The remaining
aqueous mixture was extracted with CH.sub.2Cl.sub.2 (3.times.50 mL) and, the combined extracts were dried (Na.sub.2SO.sub.4) and concentrated. Drying under vacuum provided the title compound (220 mg, 43% yield) as a colorless oil: LC-MS [M+Na] 358, 360.

B5E. Methyl 2-((4S,5S)- and ((4R,5R)-3-cyano-4-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-- yl)phenyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: A flask containing a suspension of methyl
2-(1-(4-bromophenyl)-3-cyano-4-methyl-4,5-dihydro-1H-pyrazol-5-yl)acetate (212 mg, 0.631 mmol), bis(pinacolato)diboron (184 mg, 0.717 mmol) and potassium acetate (216 mg, 2.179 mmol) in DMF (1.4 mL) was evacuated and backfilled with Ar and then sonicated
in an ultrasound bath for 5 min while under Ar. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (26 mg, 0.032 mmol) was added and the mixture was heated to 80.degree. C. The reaction mixture was stirred at this
temperature for 5.5 h and then allowed to cool down to rt. Sat'd NaHCO.sub.3 (4 mL) was added dropwise followed by EtOAc (10 mL). The mixture was filtered through Celite and the filter cake was rinsed with EtOAc (40 mL). The resulting biphasic mixture
was diluted with 5% NaHCO.sub.3 (10 mL) and shaken. The organic layer was washed with water (50 mL) and sat'd NaCl (50 mL), dried (Na.sub.2SO.sub.4) and evaporated. Chromatography (SiO.sub.2, 4/1 Hex/EtOAc) of the crude afforded the title compound (117
mg, 48.4% yield) as a colorless oil: LC-MS [M+H] 384.

B8B. Methyl 2-((4S,5S)-1-(4-((1-(3-methoxyphenyl)piperidin-4-yl)methyl)phenyl)-4-meth- yl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: A suspension of 3-methoxyphenylboronic acid (26 mg, 0.166 mmol), copper(II) acetate monohydrate
(5.0 mg, 0.025 mmol) and powdered molecular sieves (4A, <5 micron, activated, 96 mg) in CH.sub.2Cl.sub.2 (0.6 mL) was stirred for 6 min at rt. To this stirring suspension was added a solution of methyl
2-((4S,5S)-4-methyl-1-(4-(piperidin-4-ylmethyl)phenyl)-3-(trifluoromethyl- )-4,5-dihydro-1H-pyrazol-5-yl)acetate (41 mg, 0.097 mmol) in CH.sub.2Cl.sub.2 (0.3 mL). The reaction mixture was heated to 30.degree. C. and stirred under air (balloon) for 28
h. After this time, the mixture was filtered through Celite and the filter cake was rinsed with EtOAc (80 mL). The combined filtrate and rinse were concentrated and the residue was chromatographed (SiO.sub.2, 7/3 Hex/EtOAc) to give 20 mg of contaminated
product which was further purified by RP-HPLC (MeOH--H.sub.2O-TFA). Fractions containing the title compound were combined, basified with solid NaHCO3 and partially evaporated at to remove most of the MeOH. The remaining aqueous mixture was extracted
with CH.sub.2Cl.sub.2 (3.times.30 mL) and, the combined extracts were dried (Na.sub.2SO.sub.4) and concentrated. Drying under vacuum provided the title compound (14.0 mg, 28.7% yield) as a colorless oil: LC-MS [M+H] 504.

B9A. Methyl 2-((4S,5S)-1-(4-((1-(2-methoxypyridin-4-yl)piperidin-4-yl)methyl)phenyl)-- 4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a stirred solution of 4-bromo-2-methoxypyridine (20 mg, 0.106 mmol) and methyl
2-((4S,5S)-4-methyl-1-(4-(piperidin-4-ylmethyl)phenyl)-3-(trifluor- omethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (24.2 mg, 0.057 mmol) in DMSO (0.2 mL) was added potassium carbonate (31 mg, 0.222 mmol). The mixture was heated to 93.degree. C. and
stirred at this temperature for 20.8 h. After this time, the mixture was cooled to rt and treated with .about.1.1M HCl/MeOH, MeOAc solution [6.5 mL, prepared by addition of AcCl (0.5 mL) to MeOH (6.0 mL) at 0.degree. C. and then stirring at rt for 20
min]. The resulting solution was allowed to stand at rt for 16 h, and then diluted with MeCN (6 mL) and evaporated. The residue was taken up in EtOAc (50 mL) and, washed with sat'd NaHCO.sub.3 (2.times.30 mL), water (2.times.40 mL) and sat'd NaCl (30
mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated, and the resulting crude was purified by RP-HPLC (MeOH--H.sub.2O-TFA). Fractions containing the desired product were combined, basified with solid NaHCO.sub.3 and partially evaporated
at rt to remove most of the MeOH. The remaining aqueous mixture was extracted with CH.sub.2Cl.sub.2 (3.times.30 mL) and, the combined extracts were dried (Na.sub.2SO.sub.4) and concentrated. Drying under vacuum provided the title compound (7.0 mg,
24.24% yield) as a colorless oil: LC-MS [M+H] 505.

B10A. Methyl 2-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-yl)methyl- )phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a stirred solution of methyl
2-((4S,5S)-4-methyl-1-(4-(piperidin-4-ylmethyl)phenyl)-3-(trifluoromethyl- )-4,5-dihydro-1H-pyrazol-5-yl)acetate (25 mg, 0.059 mmol) and 4-bromo-5-chloro-2-methoxypyridine (81B, 20 mg, 0.090 mmol) in DMSO (0.3 mL) under Ar was added
N,N-diisopropylethylamine (0.041 mL, 0.237 mmol) dropwise. The mixture was heated to 92.degree. C. and stirred at this temperature for 19.5 h. After this time, the mixture was cooled to rt and treated with .about.1.1M HCl/MeOH, MeOAc solution [6.5 mL,
prepared by addition of AcCl (0.5 mL) to MeOH (6.0 mL) at 0.degree. C. and then stirring at rt for 20 min]. The resulting solution was allowed to stand at rt for 7.5 h, and then diluted with MeCN (10 mL) and evaporated. The residue was taken up in
EtOAc (50 mL) and, washed with sat'd NaHCO.sub.3 (2.times.30 mL), water (2.times.40 mL) and sat'd NaCl (30 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude (38.3 mg) was purified by chromatography (SiO.sub.2, 9/1 to 4/1
Hex/EtOAc) to give the title compound (10.8 mg, 33.2% yield) as a colorless oil: LC-MS [M+H] 539, 541.

B11A. 3-Benzyl-8-methylene-3-azabicyclo[3.2.1]octane: To a suspension of methyltriphenylphosphonium bromide (774 mg, 2.145 mmol) in THF (8.7 mL) at 0.degree. C. was added 2.5M butyl lithium/toluene (0.83 mL, 2.075 mmol) and the mixture was
stirred at 0.degree. C. for 35 min. A solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (300 mg, 1.393 mmol) in THF (2.90 mL) was added dropwise and the resulting suspension was allowed to warm up to rt over 3.5 h while stirring. The reaction was
stirred for an additional 1.0 h at rt and then quenched with sat'd NH.sub.4Cl (20 mL). The aqueous mixture was extracted with EtOAc (1.times.50 mL and then 2.times.30 mL). The combined organic layers were washed with sat'd NaCl (30 mL), dried
(Na.sub.2SO.sub.4) and evaporated. The crude was chromatographed (SiO.sub.2, 95/5 to 9/1 CH.sub.2Cl.sub.2/Ether) to afford the title compound (302 mg, 98% yield) as a colorless liquid: LC-MS [M+H] 214.

B11B. N-Cbz 8-methylene-3-azabicyclo[3.2.1]octane: To a solution of the 3-benzyl-8-methylene-3-azabicyclo[3.2.1]octane (301 mg, 1.355 mmol) in 1,2-DCE (5.4 mL) was added benzyl chloroformate (0.41 mL, 2.73 mmol) and the resulting solution was
stirred at rt for 24 h. After this time, the mixture was heated to 45.degree. C. and stirred at this temperature for 19 h. The reaction temperature was increased to 64.degree. C. and stirring was continued for 28 h. Additional benzyl chloroformate
(0.15 mL, 0.998 mmol) was added and the mixture was stirred at 64.degree. C. for an additional 14 h. At this time, the reaction mixture was evaporated and the residue was chromatographed (SiO.sub.2, 9/1 Hex/EtOAc) to provide the title compound (333 mg,
94% yield) as a colorless liquid: LC-MS [M+H] 258.

B11C. (1R,5S,8S)-benzyl 8-(4-((4S,5S)-5-(2-methoxy-2-oxoethyl)-4-methyl-3-(trifluoromethyl)-4,5-d- ihydro-1H-pyrazol-1-yl)benzyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (colorless oil, 11% yield) and methyl
2-((4S,5S)-1-(4-((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl)-4- -methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (yellowish oil, 64% yield) were prepared by following the procedure for methyl
2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)methyl)pheny- l)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (100E) but replacing 1-(2-fluoro-5-methoxyphenyl)-4-methylenepiperidine (Example 100C) by N-Cbz
8-methylene-3-azabicyclo[3.2.1]octane. Purification and separation of products were accomplished by RP-HPLC (MeOH--H.sub.2O-TFA). Fractions containing the products were basified with solid Na.sub.2CO.sub.3 and partially evaporated at rt to remove most
of the MeOH. The remaining aqueous mixtures were each extracted with CH.sub.2Cl.sub.2 (3.times.30 mL) and, the extracts were dried (Na.sub.2SO.sub.4) and concentrated: LC-MS [M+H] 558 and LC-MS [M+H] 424 respectively.

B13A. Methyl 2-((4S,5S)-1-(4-(((1R,5S,8S)-3-(5-chloro-2-methoxypyridin-4-yl)-3-azabicy- clo[3.2.1]octan-8-yl)methyl)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihyd- ro-1H-pyrazol-5-yl)acetate: To a stirred solution of methyl
2-((4S,5S)-1-(4-((1R,5S,8S)-3-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl)-4- -methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (24 mg, 0.057 mmol) and 4-bromo-5-chloro-2-methoxypyridine (18 mg, 0.081 mmol) in n-BuOH (0.4 mL) was added
N,N-diisopropylethylamine (30 .mu.L, 0.173 mmol). The mixture was heated to 88.degree. C. and stirred at this temperature for 23.5 h. At this time, the reaction temperature was increased to 98.degree. C. and stirring was continued for an additional 10
h. The mixture was cooled to rt, diluted with EtOAc (40 mL) and washed with sat'd NaHCO.sub.3 (3.times.20 mL), water (20 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and evaporated. The residue was dissolved in .about.3M
HCl/MeOH, CH.sub.2Cl.sub.2, MeOAc solution [6.3 mL, prepared by addition of AcCl (1.3 mL) to a 3/2 CH.sub.2Cl.sub.2/MeOH solution (5.0 mL) at 0.degree. C. and then stirring at rt for 20 min]. The resulting solution was allowed to stand at rt for 16 h.
After this time, the solution was evaporated and the remaining oily material was stripped from MeOH (2.times.6 mL). The residue was taken up in EtOAc (40 mL) and, washed with sat'd NaHCO.sub.3 (2.times.20 mL) and sat'd NaCl (20 mL). The organic layer
was dried (Na.sub.2SO.sub.4) and concentrated. The crude (39 mg) was dissolved in CH.sub.2Cl.sub.2 (0.5 mL) and Et.sub.3N (16 .mu.L, 0.11 mmol) and BOC.sub.2O (12 mg, 0.055 mmol) were added. The resulting solution was stirred at rt for 18 h. The final
solution was diluted with EtOAc (40 mL) and washed with sat'd NaHCO.sub.3 (2.times.20 mL) and sat'd NaCl (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. This last crude (42.2 mg) was chromatographed (SiO.sub.2, 7/3 Hex/Ether)
to give the title compound (8.0 mg, 23.7% yield) as a white solid: LC-MS [M+H] 565, 567.

B21A. 2-((4-Hydroxypiperidin-1-yl)sulfonyl)benzonitrile: To piperidin-4-ol (890 mg, 8.80 mmol), dichloromethane (10 mL), and triethylamine (3.01 mL, 21.60 mmol) at 0.degree. C. under nitrogen was added 2-cyanobenzene-1-sulfonyl chloride (1613
mg, 8 mmol) over 2-3 minutes to produce an off-white suspension. The ice bath was removed and the mixture was then allowed to warm to rt. After 8 days at rt the reaction mixture was added to 10 mL of CH.sub.2Cl.sub.2 and 10 mL of 4 N aqueous HCl,
mixed, and allowed to settle. The lower organic layer was with 2.times.10 mL additional 4 N HCl then 3.times.5 mL of water, dried with MgSO4, filtered, and concentrated in vacuo to provide the title compound (pale amber oily foam, 430 mg, 20%). LC-MS
Anal. Calc'd for C.sub.12H.sub.14N.sub.2O.sub.3S: 266.07, found [M+Na] 267.1.

B21B. Methyl 2-((4S,5S)-1-(4-((1-((2-cyanophenyl)sulfonyl)piperidin-4-yl)oxy)phenyl)-4- -methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of triphenylphosphine (29.0 mg, 0.111 mmol) and DMF (0.5 mL) added
(E)-diethyl diazene-1,2-dicarboxylate (0.015 mL, 0.095 mmol). After stirring for 5 min this mixture was added to the thick 2-((4S,5S)-1-(4-hydroxyphenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1- H-pyrazol-5-yl)acetate (25 mg, 0.079 mmol) and stirred
for 5 min. To this amber solution was then added 2-((4-hydroxypiperidin-1-yl)sulfonyl)benzonitrile (21.05 mg, 0.079 mmol) and the mixture capped under nitrogen. The mixture was placed in a 100.degree. C. oil bath for 2 h. After cooling to rt, 1 mL of
water plus 1 mL of brine and 2 mL of EtOAc were added to the reaction mixture, mixed, and allowed settle. The lower aqueous layer was removed and then the organic was washed with two more 2 mL of 50% brine/water then 2 mL of water. The EtOAc was
concentrated to an oil and purified by prep LC using the system below to provide product (yellow oil, 12 mg, 26.9%). LC-MS Anal. Calc'd for C.sub.26H.sub.27F.sub.3N.sub.4O.sub.5S: 564.17, found [M+Na] 565.1.

B36A. tert-Butyl 3-vinylazetidine-1-carboxylateTo a solution of methyltriphenylphosphonium bromide (3.86 g, 10.80 mmol) in THF (6 mL) at -78.degree. C. was added butyllithium (1.080 mL, 10.80 mmol) and stirred for 20 min before being warmed up
to 0.degree. C. and stirred 1 h before tert-butyl 3-formylazetidine-1-carboxylate (1 g, 5.40 mmol) in THF (3 mL) was added. The reaction continued stirring at 0.degree. C. for 2 h and then at rt for 3 h. After quenched with NH.sub.4Cl (sat.), the
reaction was extracted with EtOAc (3.times.), washed with saturated aqueous NaCl. The organic was dried and concentrated. Purification via silica gel chromatography with 0-70% EtOAc/hexanes gave the title compound as a white oil (0.5 g, 50% yield).
LC-MS Anal. Calc'd for C.sub.10H.sub.17NO.sub.2 183.1, found [M+H] 184.0.

B36B. tert-Butyl 3-(4-((4S,5S)-5-(cyanomethyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H- -pyrazol-1-yl)phenethyl)azetidine-1-carboxylate: To a solution of tert-butyl 3-vinylazetidine-1-carboxylate (300 mg, 1.637 mmol) in THF (0.6 mL) was
added 9-BBN (3.27 mL, 1.637 mmol) under argon and stirred at 68.degree. C. for 1.5 h. Cooled to rt, the resulting mixture was added into vigously stirred mixture of 2-((4S,5S)-1-(4-bromophenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H--
pyrazol-5-yl)acetonitrile (584 mg, 1.686 mmol), (1,1-bis(diphenylphosphino)ferrocene}dichloropalladium(II), complex with dichloromethane (66.8 mg, 0.082 mmol) and potassium carbonate (453 mg, 3.27 mmol) in DMF (2 mL) and H.sub.2O (0.2 mL) and then
stirred at 65.degree. C. for 3 h. The reaction was poured into water and its pH was adjusted >11, then was extracted with CH.sub.2Cl.sub.2 (3.times.). The organic was dried over MgSO.sub.4 and concentrated. Purification via silica gel
chromatography with 0-50% EtOAc/hexanes gave the title compound as white oil (400 mg, 54.2%). LC-MS Anal. Calc'd for C.sub.23H.sub.29F.sub.3N.sub.4O.sub.2 450.4, found [M+H] 451.0.

B37B. tert-Butyl 8-hydroxy-5-azaspiro[2.5]octane-5-carboxylate To a suspension of tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (260 mg, 0.808 mmol) in ethyl alcohol (3 mL) at 0.degree. C. was added sodium borohydride (32.2 mg, 0.808
mmol) and stirred at rt for 16 h. After concentration in vacuo, CH.sub.2Cl.sub.2 (5 mL) was added and then quenched with 5 mL H.sub.2O. The organic layer was collected and the aqueous layer was back extracted with CH.sub.2Cl.sub.2 (2.times.5 mL). The
combined extract was dried over Na.sub.2SO.sub.4 and concentrated. Purification via flash chromatography (0-70% EtOAc/hexanes) afforded the title compound as white oil (149 mg, 81% yield).

B37C. tert-Butyl 8-(4-((4S,5S)-5-(2-methoxy-2-oxoethyl)-4-methyl-3-(trifluoromethyl)-4,5-d- ihydro-1H-pyrazol-1-yl)phenoxy)-5-azaspiro[2.5]octane-5-carboxylate: The intermediate was prepared following the procedure of Example B30.

B37D. Methyl 2-((4S,5S)-1-(4-(5-azaspiro[2.5]octan-8-yloxy)phenyl)-4-methyl-3-(trifluo- romethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of tert-butyl 8-(4-((4S,5S)-5-(2-methoxy-2-oxoethyl)-4-methyl-3-(trifluoromethyl)-4,5-d-
ihydro-1H-pyrazol-1-yl)phenoxy)-5-azaspiro[2.5]octane-5-carboxylate (34 mg, 0.065 mmol) in CH.sub.2Cl.sub.2 (0.6 mL) was added hydrogen chloride (0.065 mL, 0.065 mmol) and stirred at rt for 16 h. After neutralized with saturated aqueous NaHCO.sub.3, the
organic layer was collected, dried over Na.sub.2SO.sub.4 and concentrated. Used for next step reaction without further purification. LC-MS Anal. Calc'd for C.sub.21H.sub.26F.sub.3N.sub.3O.sub.3 425.19, found [M+H] 426.0.